The ESCRT machinery is recruited by the viral BFRF1 protein to the nucleus-associated membrane for the maturation of Epstein-Barr Virus

PLoS Pathog. 2012 Sep;8(9):e1002904. doi: 10.1371/journal.ppat.1002904. Epub 2012 Sep 6.


The cellular endosomal sorting complex required for transport (ESCRT) machinery participates in membrane scission and cytoplasmic budding of many RNA viruses. Here, we found that expression of dominant negative ESCRT proteins caused a blockade of Epstein-Barr virus (EBV) release and retention of viral BFRF1 at the nuclear envelope. The ESCRT adaptor protein Alix was redistributed and partially colocalized with BFRF1 at the nuclear rim of virus replicating cells. Following transient transfection, BFRF1 associated with ESCRT proteins, reorganized the nuclear membrane and induced perinuclear vesicle formation. Multiple domains within BFRF1 mediated vesicle formation and Alix recruitment, whereas both Bro and PRR domains of Alix interacted with BFRF1. Inhibition of ESCRT machinery abolished BFRF1-induced vesicle formation, leading to the accumulation of viral DNA and capsid proteins in the nucleus of EBV-replicating cells. Overall, data here suggest that BFRF1 recruits the ESCRT components to modulate nuclear envelope for the nuclear egress of EBV.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium-Binding Proteins / metabolism
  • Calcium-Binding Proteins / physiology
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology
  • Cell Line, Tumor
  • Cell Nucleus / metabolism*
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Endosomal Sorting Complexes Required for Transport / physiology
  • Gene Expression Regulation, Viral / physiology
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / metabolism
  • Herpesvirus 4, Human / physiology*
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Membrane Proteins / physiology
  • Nuclear Envelope / metabolism*
  • Protein Binding / genetics
  • Protein Transport
  • Tissue Distribution
  • Transfection
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*
  • Viral Proteins / physiology
  • Virus Assembly / genetics
  • Virus Assembly / physiology*
  • Virus Release / genetics
  • Virus Release / physiology


  • BFRF1 protein, Human herpesvirus 4
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Membrane Proteins
  • PDCD6IP protein, human
  • Viral Proteins

Grant support

This study was supported by grants NHRI-EX99-9928BI from National Health Research Institutes (, grants NSC98-2320-B002-054-MY3 and NSC100-2320-B-227-002-MY2 from National Science Council ( and grant 99R40044 from National Taiwan University (, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.